Process for crystallizing L-alpha-aspartyl-L-phenyl-alanine methyl

ABSTRACT

A crystalline L-alpha-aspartyl-L-phenyl-alanine methyl ester product is disclosed. The product is obtained by crystallizing the ester from an aqueous solution, by cooling. The initial concentration of ester in the aqueous solution used provides at least 10 grams of precipitated solid phase per liter of solution. The solution is cooled through conductive heat transfer without effecting forced flow to form a sherbet-like pseudo solid phase.

This application is a continuation of application Ser. No. 07/054,494,filed on May 27, 1987, now abandoned, which is a division of applicationSer. No. 06/839,819, filed 3/12/86, now abandoned, which is acontinuation of application Ser. No. 06/482,542, filed 4/6/83, nowabandoned.

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to a process for crystallizing and separatingL-α-aspartyl-L-phenylalanine metyl ester under some specificcrystallization conditions.

L-α-aspartyl-L-phenylalanine methyl ester (hereinafter abbreviated asAPM) is a substance which is expected to find wide applications as a newlow-calorie sweetener due to its good sweetening properties. Asprocesses for industrially producing this APM, the following processesare typical.

That is, there are known a process of binding an N-substituted asparticacid anhydride with phenylalanine methyl ester in an organic solvent(U.S. Pat. No. 3,786,039), a process of directly binding a strong acidaddition salt of aspartic acid anhydride with phenylalanine methyl ester(Japanese Patent Publication No. 14217/74), a process of condensing anN-substituted aspartic acid with phenylalanine methyl ester in thepresence of an enzyme and eliminating the substituent (Japanese PatentPublication No. 135595/80), and the like.

In industrial production, a crystallizing step to isolating APM from areaction solution is necessary for obtaining the final product in any ofthe processes described above. This crystallizing step is usuallyconducted, for example, by re-dissolving a crude product in water, aorganic solvent or an aqueous organic solvent, cooling the solutionthrough heat exchange with a refrigeration medium (forced cyclizationtype indirect cooling system) or evaporating part of the solvent underreduce pressure (self-evaporating system) using a crystallizer equippedwith a stirring means, and dewatering and filtering out the thusprecipitated crystals by means of a centrifugal separator or the like.

However, the thus obtained APM crystals are fine needle-like crystals,and therefore show extremely bad solid-liquid separability in filtrationand dewatering procedure. Thus the above-described processes havepractical problems.

To illustrate one case, when 600 liters of a slurry containing APMcrystals obtained by one of the above-described processes (seeComparative Example) was subjected to solid-liquid separation byfiltering for 2 hours and dehydrating for one hour in a centrifugalseparator having a diameter of 36 inches and a volume of 92 liters(number of revolutions: 1,100 r.p.m.; centrifuging effect: 600 G), theresulting cake had a water content of 45 to 50% or more. The watercontent as used herein is defined as (water amount in the cake/wholeamount of wet cake)×100%.

In addition, there is found another defect that, when a series of theprocedures of scraping this cake and conducting solid-liquid separationof a fresh slurry containing APM crystals are repeated, the base layerof cake between so tightly hardened that its removal requires much laborand time.

Further, in a drying step following the crystallizing step, the dryingload is too high due to the high water content of the cake, and theresulting powder has such large bulk specific volume that it isextremely difficult to handle.

Table 1 shows powder properties of APM crystals obtained by thecrystallizing process of the present invention (see Example 1) and thatobtained by one conventional process (see Comparative Example).

                  TABLE 1                                                         ______________________________________                                                          Con-                                                                          ventional                                                                             Process of                                                            Process the Invention                                       ______________________________________                                        Static (loose) specific volume (cc/g)                                                             6-7       3-4                                             Close (packed) specific volume (cc/g)                                                             3-4       2-3                                             Rate of dissolution (min.)                                                                        14-17     5-6                                             ______________________________________                                    

in crystallizing other materials, it has been known that theabove-described problems in the crystallizing procedure can be removedby conducting the crystallization employing a low concentration and aslow cooling rate to obtain crystals having a large diameter. With APMcrystals, however, such crystallization procedure results in formationof needle-like crystals growing only in a longitudinal direction,failing to provide expected effects. For example, when seed crystalswere added to a 0.8 wt % APM solution and the solution temperature wasdecreased from 15° C. to 5° C. in two days, crystals grew 214% in thelength direction but only 15% in the diameter direction.

As a result of intensive investigations to improve workability of theaforesaid step in the production of APM by examining various conditions,the inventors have found the following novel facts.

That is, surprisingly, it has been found that, in crystallizing APM fromits solution of a certain concentration or above by cooling withoutstirring, APM crystals take up the solvent into the space formed amongthem, and the whole solution thus appears apparently solidified, andthat the crystals obtained in this state show extremely good propertiesin subsequent solid-liquid separation procedure. Observation of thecrystals under a scanning type electromicroscope revealed that severalneedle-like crystals are bundled to form apparently one crystal (to bedescribed hereinafter).

The bundle-like crystal aggregates of the present invention areextremely strong against physical impact as long as they are not undergrowing in a supersaturated solution, and have been confirmed tomaintain 5- to 10-fold or more diameter as compared to that ofconventional crystals even after being transported, separated or dried.

More surprisingly, even under such crystallizing condition in which,with ordinary substances, crystals fixedly deposit on aheat-transferring surface to cause so-called scaling which isdifficultly removable, precipitation of APM crystals in accordance withthe present invention is found to allow complete removal of the crystallayer from the cooling surface.

As a result of intensive investigations to apply the above-describedfindings to an actual process, the inventors have achieved remarkableimprovement in workability in the step of precipitating APM crystalsfrom an APM solution by cooling the solution under the condition offorming a pseudo solid phase to obtain crystals showing goodseparability, thus having completed a novel crystallizing processproviding industrially great economical effects. As a result of furtherinvestigations, the inventors have found that, once the solution takes apseudo solid phase, it can maintain its good separability even whensubjected to a desupersaturation procedure of rapid cooling accompaniedby causing forced flow, which serves to increase the efficiency of thestep and improve crystallization yield, thus having completed thepresent invention.

That is, a characteristic aspect of the present invention is to obtainbundled, large-diameter APM crystal aggregates by cooling as fast aspossible an APM aqueous solution employing such crystallizing conditionsor crystallizers that natural heat transfer by convection is realizedonly in the very early stage of the crystallizing step, then heattransfer is controlled by conduction. According to the presentinvention, solid-liquid separability and powder properties of theproduct can be improved, workability in each step being remarkablyimproved. Therefore, the present invention provides an APM-crystallizingprocess which is economically quite advantageous. Additionally, due tothe above-described properties of the present invention, APM crystalshaving bad crystal habit can be converted to APM crystals having goodcrystal habit by the recrystallization process in accordance with thepresent invention, and APM containing impurities such asdiketopiperazine (DKP), an cyclized product of APM, andL-α-aspartyl-L-phenylalanine can be freed of the impurities bysubjecting the impurities-containing APM to the crystallizing process ofthe present invention coupled with a decrease in the amount of adheringmother liquid in a solid-liquid separation and improvement in cakewashability.

The present invention will now be described in more detail below.

In the process of the present invention, cooling is conducted withoutforced flow caused, for example, by mechanical stirring. Additionally,it is desirable to render the whole solution into a sherbet-like pseudosolid phase to finish natural flow phenomenon resulting from temperaturedistribution as fast as possible. For the purpose of comparison,electronmicroscopic photographs of bundled crystals obtained by theprocess of the present invention (FIG. 1A (×58), and FIG. 1B (×580)),fine crystals obtained by indirect cooling under forced flow, one of theconventional processes (FIG. 2A (×560) and FIG. 2B (×1280)), anddendrite crystals obtained without causing forced flow and under suchcondition that no sherbet is formed (FIG. 3A (×51) and FIG. 3B (×350)).From these photographs, it can be easily understood that the threecrystals, which show the same results in X-ray powder diffractiometry,are clearly different from each other in shape and size due to thedifference in crystallizing manner.

As a crystallizer for satisfying the above-described procedureconditions, FIG. 4 shows an example of continuous crystallizers, inwhich a jacketed U-tube having nozzles on both ends is used. Uponinitiation of the crystallizing procedure, a feed solution is previouslycharged in the tube before initiation of cooling. At a stage wherecrystallization has proceeded in the tube, feed solution is pressed intothe tube through feed inlet 1 at a slow rate, upon which a sherbet-likeslurry is pressed out of the tube through opposite outlet 2. Thesherbet-like slurry can be continuously obtained onward by coolingthrough heat transfer by conduction and feeding the solution in suchflow rate that enough residence time for crystallization to be completedis attained.

Additionally, the crystallizer may not necessarily ba a U-tube, and avertical or horizontal straight tube and any curved tube that does notsuffer pressure loss more than is necessary may be employed as well.

FIG. 5 shows an example of batchwise crystallizers. Feed solution isintroduced through feed inlet 1. After completion of charging thesolution, a refrigeration medium is introduced into cooling plates 2 orcooling tube and jacket 3 to cool the contents. After a predeterminedperiod of time, discharge valve 4 is opened to discharge a sherbet-likeslurry.

FIGS. 6 and 7 show examples of conducting the process of the presentinvention using a conventional apparatus. Procedures are continuous inboth cases.

In FIG. 6, a rotating steel belt is used as a cooling surface (the beltbeing cooled, for example, by blowing a refrigeration medium to the backof the belt), and a feed solution is continuously introduced onto thebelt to crystallize. The formed sherbet-like slurry is recovered byscraping with scraper 1 provided on the other end. In this embodiment,for the purpose of forming a thick sherbet layer on the belt, guides 2may be provided on the sides of the belt, or a frame may be fixedlyprovided on the belt to thereby prevent the solution from flowing overbefore solidifying. In some cases, semi-continuous procedure may beemployed.

FIG. 7 shows an embodiment of utilizing an evaporate-condenser. A feedsolution is introduced to the center 3 of two contact-rotating drums 1rotating outward. The drums are cooled from inside with a refrigerationmedium instead of being heated from inside with steam, on which sherbetdeposits as a result of crystallization. The thus formed sherbet isscraped by scraper 2.

These embodiments are particularly designed or intended for satisfyingthe aforesaid special conditions of the crystallization to be employedin the process of the present invention. The inventors do not know thatthe above-described apparatuses have been used for crystallizing APM aswell as other materials through heat transfer by conduction. Processesfor crystallizing APM with the use of any other apparatuses whichsatisfy the specific crystallization conditions of this invention are ofcourse within the scope of this invention.

To attain an apparantly solidified state, the solution must containabout 10 g or more solids per liter of the solvent at that point. Thatis, in an aqueous solution system, satisfactory recovery of APM can beattained by cooling the system to 5° C., taking the solubility of APMinto consideration. Theoretically, an initial concentration of the APMsolution before crystallization of 1.5 wt % suffices since thesaturation concentration at the temperature is 0.5%. However, in a lowsupersaturated region, crystallizing rate is too slow. Therefore,practically the aqueous system must contain about 2 wt % or more APM forforming the sherbet state. In order to obtain crystals having largediameter, solidification must proceed at a faster rate. For thispurpose, the initial concentration is desirably about 3 wt % or more.

FIG. 8 shows the results of measuring solubility of APM in water.

On the other hand, the upper limit of the concentration depends uponstability of APM in solution at elevated temperatures and its solubleconcentration and, in the aqueous system, a concentration of about 10%or less, which is a saturation concentration of APM at 80° C., isusually a suitable upper limit.

As the crystallizing solvent, water suffices, which may optionallycontain other solvents as long as the spirit of the present invention isnot spoiled, i.e., no particular troubles take place in the practice ofthe present invention.

For effectively practicing the process of the present invention, coolingrate is an important procedure factor. However, in the cooling stepbased on heat transfer by conduction, a temperature distribution appearswithin a solution being cooled, and the cooling rate is not timewiseconstant, thus definite control of cooling rate being difficult.However, average temperature of a cooled solution after a given periodof time is decided by the temperature of the refrigeration medium used,the initial temperature of the cooled solution, and the maximum distancebetween the cooled solution and the heat-transfer surface. The initialtemperature of the cooled, solution depends upon the aforesaidconcentration of APM and, as the refrigeration medium, a known one suchas propylene glycol, ethylene glycol or cooling water may be used. Thetemperature of the refrigeration medium is most suitably -5° C. to 35°C. in view of prevention of freezing of the solvent and time requiredfor cooling. Further, as to the maximum distance between the cooledsolution and the heat-transfer surface, the larger the distance, themore the difference in crystallization degree due to greater temperaturedistribution within the cooled solution. In addition, decomposition ofAPM proceeds so much that predetermined supersaturation cannot beattained, thus separability being adversely affected to a large degree.Therefore, even the remotest part of the solution being cooling isdesirably 500 mm or less from the heat-transfer surface. In any case,those skilled in the art can easily find conditions necessary forrendering the whole solution into a pseudo solid phase in theillustrated crystallizers, which are the marrow of the presentinvention, through simple preliminary experiments.

The thus obtained sherbet-like pseudo solid phase comprising APMcrystals and the solvent does not itself show any fluidity, but showsextremely good separating properties from the cooling surface, thuscausing no troubles upon discharge out of the crystallizer. It can beeasily destroyed into a slurry, for example, by stirring and can betransported through pumps or the like.

Additionally, in the process of the present invention, cooling of thesystem is conducted through heat transfer by conduction, and hence itrequires a longer time to cool to a desired temperature than that incooling under forces flow. Needless to say, the process of the presentinvention provides more advantages than compensate for the disadvantage.However, in order to more raise efficiency and improve yield, it ispossible to conduct desupersaturating procedure subsequent to theaforesaid crystallizing step.

That is, the sherbet-like pseudo solid phase obtained by crystallizationthrough heat transfer by conduction and comprising APM crystals and thesolvent is rapidly cooled subsequent to destruction of the solid phase,for example, by stirring to thereby remove residual supersaturation in ashort time. However, where the proportion of APM crystals additionallyprecipitated in the desupersaturating procedure accounts for about 25%or more the whole solid phase APM finally obtained, solid-liquidseparability of the slurry is sharply deteriorated. Therefore, thedesupersaturation to be carried out is desirably controlled to less thanthe above-described degree.

The present invention will now be described in more detail by thefollowing non-limiting examples of preferred embodiments of the presentinvention.

EXAMPLE 1

This example was conducted using an apparatus shown in FIG. 9.

380 Liters of a feed solution containing dissolved therein 17.7 Kg ofAPM (containing 3% DKP) (55° C.; initial concentration of APM: 4.4 wt %)was charged in a stainless steel crystallizer having a diameter of 400mm (maximum distance between the cooled solution and the coolingsurface: 75 mm) and having jacket 3 and inner cooling plates 2, and a 0°C. refrigeration medium was circulated through the jacket and thecooling plates to conduct cooling for 3 hours, during which coolingthrough heat transfer by conduction became predominant about 15 minutesafter initiation of the cooling. The whole solution became a pseudosolid phase after about one hour.

Thereafter, the contents were discharged into tank 7 equipped withcooling coil 5 and stirrer 6 to destroy the solid phase. On thisoccasion, the average temperature of the slurry was about 16° C., andthe APM concentration of the mother liquid was 0.9 wt %. Then, arefrigeration medium was introduced into the coil under further stirringto conduct cooling for one hour to thereby lower the temperature of theslurry to about 7° C. The APM concentration of the mother liquor was 0.7wt %.

When the thus obtained slurry was filtered and dewatered using acentrifugal separator 8 having a diameter of 36 inches, water content ofthe cake decreased to 25% after only 20 minutes. Yield: 19 Kg (wet);recovery ratio: 86%; DKP content: 0.1%.

Additionally, APM crystals additionally precipitated in thedesupersaturation procedure accounted for about 5% of the whole solidphase finally obtained.

Similar results were obtained by crystallizing APM using an apparatushaving a cooling tube in place of the cooling plate.

With a slurry obtained by a conventional process (see ComparativeExample to be described below), the water content was as high as 45 to50% even after 2-hour filtration and 1-hour dewatering (3 hoursaltogether).

COMPARATIVE EXAMPLE

This comparative example was conducted using an apparatus shown in FIG.10. A feed solution was continuously introduced through feed inlet 8.Two stainless steel tanks 4 (volume: 100 liters) equipped with stirrer1, outer heat-exchanger 2, and jacket 3 were used in series. Stirringspeed was 50 r.p.m. APM concentration of the feed solution was 4.4 wt %,and the flow rate was 60 liters/hr. The average temperature in the firsttank was 25° C., and that in the second tank 10° C. Additionally, inFIG. 10, numeral 5 designates a receiving tank equipped with stirrer 1and cooling coil 6, and 7 designated a centrifugal separator.

Results of comparing the process of the present invention with theconventional process with respect to centrifuge-filtration rate andcentrifuge dewatering rate are shown in FIG. 11A and FIG. 11B,respectively. -- shows the measured values with APM slurry in accordancewith the present invention, and -- shows the measured values with APMslurry obtained by the conventional process.

In leaf test by suction filtration to determine specific resistancevalue, the APM slurry obtained by the process of the present inventionshowed a specific resistance of 1×10⁸ to 2×10⁸ m/Kg immediately afterbeing discharged and 3×10⁸ to 5×10⁸ m/Kg after desupersaturation,whereas the slurry obtained by the conventional process showed aspecific resistance of 5×10¹⁰ to 1×10¹¹ m/Kg.

EXAMPLE 2

A feed solution having the same composition as in Example 1 was cooledusing a steel belt cooler (1.2 m×5 m; made of stainless steel) as shownin FIG. 12 to crystallize APM. The feed solution was continuouslyintroduced onto the belt through feed inlet 3. Where the feed amount islarge, it is preferable to provide guides 2 on the sides of the belt forpreventing overflow. In such cases, the guides are not necessarilyprovided over the full length of the belt, because the solution does notflow out after being rendered sherbet-like.

Cooling was conducted indirectly by jetting 12° C. cooling water on toback of the belt. The solution-feeding rate and the belt speed wereadjusted so that the thickness of sherbet, or maximum distance from thecooling surface, became about 10 mm.

The thus obtained sherbet containing APM crystals and water was scrapedout by scraper 1 and destroyed in receiving tank 4 by stirring (60r.p.m.) into a slurry. The average temperature of the productimmediately after scraping was about 18° C. Additionally, cooling fordesupersaturation was not particularly conducted in the receiving tank.

When about 100 liters of the slurry in the receiving tank was subjectedto solid-liquid separation in centrifugal separator 5, the water contentof cake was reduced to about 30% after 30 minutes. Yield: 4.3 Kg. Theseparated mother liquor contained about 1.5 wt % APM. Recovery ratio:68%.

This steel-belt cooler system has the advantages that, as compared tothe system of Example 1, the cooling surface can be smaller due tolarger processing speed and that, in view of process flow, the feedsolution is not necessarily kept at high temperature because ofcontinuous system, thus decomposition of APM being remarkably reduced.

As is clear from the above descriptions and examples, application of theprocess of the present invention to crystallization and separation ofAPM crystals provides the following outstanding advantages from theindustrial point view as compared to conventional processes, forexample, of forced circulation-outer cooling system or self evaporationsystem, though energy load required for cooling, etc. is almost thesame.

(1) As to solid-liquid separation of a slurry containing APM crystals, aslurry obtained by the conventional process is difficult to reduce inits water content to the degree attained by a slurry obtained by theprocess of the present invention even when the separation time isprolonged.

(2) In repeatedly conducting the above-described separation procedure, aslurry obtained by the conventional process suffers tightpress-solidification of the cake base layer, its removal requiring muchlabor, whereas a slurry obtained by the process of the present inventiondoes not undergo such a phenomenon. For example, in one embodiment ofthe process of the present invention, the base layer could be easilyremoved from the filter surface even after 20 times repeating theprocedure, whereas repeated procedure according to the conventionalprocess resulted in tight solidification only after 5 times repeatingthe procedure, the thus solidified base layer being difficultyremovable.

(3) To evaluate the shortening of filtration time and reduction orseparation load such as cake removal, realized by applying the processof the present invention, in terms of required filter area, the processof the present invention reduced the area to about 1/10 of less of thearea of the conventional process.

(4) Additionally, the remarkable improvement of separability isaccomplished by reduction of adhesion of impurity-containing motherliquid onto the crystals to 1/2 and improvement of washing effect, andhence crude crystallization step may be eliminated by combining cakewashing procedure or the like.

(5) Load in a drying step is decreased to about 5/8. For example, dryingload necessary for obtaining 100 Kg of dry product powder (watercontent: 3%) is as follows. With APM crystals containing 50% water andobtained by the conventional process, the load is 5.1×10⁴ Kcal, withneglecting loss in heat transfer procedure, whereas with APM crystalscontaining 25% water and obtained by the process of the presentinvention, it is 1.6×10⁴ Kcal.

(6) Dry powder properties are so remarkably improved as shown in Table 1that handling properties of the powder are improved.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A and FIG. 1B are electromicroscopic photographs of APM crystalsobtained by the process of the present invention.

FIG. 2A and FIG. 2B are electronimicrographs of APM crystals obtained bythe conventional process.

FIG. 3A and FIG. 3B are electron microscope photographs of APM crystalsobtained without causing forced flow and under such condition that nosherbet is formed.

FIGS. 4, 5, 6, and 7 show examples of crystallizers to be used in thepresent invention.

FIG. 8 shows solubility of APM in water.

FIG. 9 shows a crystallizer used in Example 1.

FIG. 10 shows a crystallizer used in conventional process.

FIG. 11A and FIG. 11B show the results of comparing the process of thepresent invention with a conventional process with respect to filtrationrate and dehydration rate of APM slurry.

FIG. 12 shows a crystallizer used in Example 2.

What is claimed is:
 1. In an industrial-scale crystallineL-alpha-aspartyl-L-phenylalanine methyl ester product obtained byindustrial-scale crystallization of L-alpha-aspartyl-L-phenylalaninemethyl ester from an aqueous solution ofL-alpha-aspartyl-L-phenylalanine methyl ester by cooling, theimprovement comprising using a crystallization process comprising thesteps of:(1) preparing an industrial-scale aqueous solution ofL-alpha-aspartyl-L-phenylalanine methyl ester, adjusting the initialconcentration of the said ester in the solution so that the amount ofprecipitated solid phase formed after cooling is about 10 grams, ormore, per liter of solvent; (2) charging the solution into acrystallizer equipped with solid cooling surfaces comprising coolingplates or cooling tubes, and a cooling jacket, to cool the aqueoussolution without effecting forced flow and by conductive heat transfer,by contacting the solution with the cooling surfaces having arefrigeration medium circulating therein at a temperature of from -5° C.to +35° C. and keeping a distance between the solution and the coolingsurface of 500 mm or less to form a sherbet-like pseudo solid phase; and(3) isolating the sherbet-like pseudo solid phase to obtain theindustrial-scale crystalline L-alpha-aspartyl-L-phenylalanine methylester product, wherein the crystals of said product have a staticspecific volume of from 3 to 4 cc gram⁻¹, a close specific volume of 2to 3 cc gram⁻¹, and a rate of dissolution, in water, of 5 to 6 minutes.2. The industrial-scale crystalline L-alpha-aspartyl-L-phenylalaninemethyl ester of claim 1, wherein the initial concentration of theL-alpha-aspartyl-L-phenylalanine methyl ester in said aqueous solutionis from 2 to 10 wt. %.
 3. The industrial-scale crystallineL-alpha-aspartyl-L-phenylalanine methyl ester product of claim 1,wherein the initial concentration of theL-alpha-aspartyl-L-phenyl-alanine methyl ester in said aqueous solutionis from 3 to 10 wt. %.
 4. The industrial-scale crystallineL-alpha-aspartyl-L-phenylalanine methyl ester product of claim 1,wherein said aqueous solution is subjected to a desupersaturationoperation carried out by cooling or effecting forced flow, afterformation of said pseudo solid phase.
 5. The industrial-scalecrystalline L-alpha-aspartyl-L-phenylalanine methyl ester product ofclaim 4, wherein the proportion of L-alpha-aspartyl-L-phenylalaninemethyl ester crystals precipitated in the desupersaturation procedure isabout 25% or less, based on the total solid phase finally obtained. 6.In a crystalline L-alpha-aspartyl-L-phenylalanine methyl ester productobtained by crystallization of L-alpha-aspartyl-L-phenylalanine methylester from an aqueous solution of L-alpha-aspartyl-L-phenylalaninemethyl ester by cooling, the improvement comprising using acrystallization process comprising of steps of:(1) preparing an aqueoussolution of L-alpha-aspartyl-L-phenylalanine methyl ester, adjusting theinitial concentration of said ester in the solution so that the amountof precipitated solid phase formed after cooling is about 10 grams, ormore, per liter of solvent; (2) charging the solution into acrystallizer equipped with solid cooling surfaces comprising coolingplates or cooling tubes, and a cooling jacket, to cool the aqueoussolution without effecting forced flow and by conductive head transfer,by contacting the solution with the cooling surfaces having arefrigeration medium circulating therein at a temperature of from -5° C.to +35° C. and keeping a distance between the solution and the coolingsurface of 500 mm or less to form a sherbet-like pseudo solid phase; and(3) isolating the sherbet-like pseudo solid phase to obtain thecrystalline L-alpha-aspartyl-L-phenylalanine methyl ester product,wherein the crystals of said product have a static specific volume offrom 3 to 4 cc gram⁻¹, a close specific volume of 2 to 3 cc gram⁻¹, anda rate of dissolution, in water, of 5 to 6 minutes.
 7. The crystallineL-alpha-aspartyl-L-phenylalanine methyl ester of claim 6, wherein theinitial concentration of the L-alpha-aspartyl-L-phenylalanine methylester in said aqueous solution is from 2 to 10 wt. %.
 8. The crystallineL-alpha-aspartyl-L-phenylalanine methyl ester product of claim 6,wherein the initial concentration of theL-alpha-aspartyl-L-phenylalanine methyl ester in said aqueous solutionis from 3 to 10 wt. %.
 9. The crystallineL-alpha-aspartyl-L-phenylalanine methyl ester product of claim 6,wherein said aqueous solution is subjected to a desupersaturationoperation carried out by cooling or effecting forced flow, afterformation of said pseudo solid phase.
 10. The crystallineL-alpha-aspartyl-L-phenylalanine methyl ester product of claim 9,wherein the proportion of L-alpha-aspartyl-L-phenylalanine methyl estercrystals precipitated in the desupersaturation procedure is about 25% orless, based on the total solid phase finally obtained.
 11. Theindustrial-scale crystalline L-alpha-aspartyl-L-phenylalanine methylester product of claim 9, wherein said product is dry.
 12. Thecrystalline L-alpha-aspartyl-L-phenylalanine methyl ester product ofclaim 6, wherein said product is dry.
 13. The industrial-scalecrystalline L-alpha-aspartyl-L-phenylalanine methyl ester product ofclaim 1, wherein the initial concentration of theL-alpha-aspartyl-L-phenylalanine methyl ester in said aqueous solutionis about 2 wt. % or more.
 14. The crystallineL-alpha-aspartyl-L-phenylalanine methyl ester product of claim 6,wherein the initial concentration of L-alpha-aspartyl-L-phenylalaninemethyl ester in said aqueous solution is about 2 wt. % or more.